Alzheimer's disease (AD) is the most common neurodegenerative disorder. There are no existing therapies that can reverse disease progression, and thus new approaches are urgently needed. Accumulation of amyloid beta (A?), a proteolytic cleavage product of amyloid precursor protein (APP), is considered the initiating step in pathogenesis, but the signaling pathways that control this process are not well defined. Synaptic activity is thought to be a key driver of APP amyloidogenic processing, but the molecular links between neuronal activity and A? production are unclear. An attractive candidate is Plk2, a synaptic activity-inducible member of the polo-like kinase (Plk) family that functions in homeostatic synaptic plasticity to weaken synapses in response to prolonged overexcitation. Plk2 is upregulated in AD brain, directly phosphorylates APP and is required for APP amyloidogenic processing in response to chronic hyperexcitation in vitro. Importantly, inhibition of Plk2 (using transgenic dominant negative interference or a small molecule Plk inhibitor) shows encouraging evidence of slowing pathogenesis in AD model mice. The physiological function of APP has remained elusive, but as a Plk2 substrate, APP may play a role in synaptic depression. We identified Plk2 phosphorylation sites within APP C-terminus that was critical for downregulation of AMPA receptors during homeostatic synaptic plasticity. Interestingly, distinct APP phosphorylation sites are required for AMPA receptor internalization during a different form of plasticity, NMDA-receptor dependent long term depression (LTD). In this proposal we will test the hypotheses that (1) pharmacological inhibition of Plk2 using 2 different small molecule inhibitors slows disease progression in mouse models of AD; (2) Plk2 plays a selective role among Plk family members in activity-regulated APP processing, as determined by analysis of conventional and conditional knockout mice for Plk1-3; and 3) APP is centrally involved in synaptic depression of AMPA receptors at excitatory synapses under diverse plasticity paradigms, triggered by different kinases (Plk2 or GSK3) signaling through a combinatorial ?phosphorylation code? in the APP C-terminus. This proposal is highly significant as it will help elucidate novel physiological mechanisms that link different forms of synaptic activity to APP amyloidogenic processing. These studies will advance basic understanding of APP function and synaptic plasticity, while uncovering and validating novel targets for therapeutic interventions in AD.